This invention generally pertains to heterocyclic carbon compounds having drug and bio-affecting properties and to their preparation and use. In particular, the invention is concerned with a series of new 2,3-dihydro-2-oxo-1H-imidazo[4,5-b]quinolinylamine derivatives which are phosphodiesterase inhibitors, blood platelet antiaggregators and cardiotonic agents. According to conventional nomenclature, the basic heterocyclic structure can be referred to as 1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-one.
As a structural class, relatively few 1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-ones are known to applicants with the following chemical literature illustrative of the art.
Kozak, et al., Bull. Intern. Acad. Polanaise, 1930A, 432-438 (Chem. Abs., 25, 5400) describes the unsubstituted compound 1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-one of formula (i). ##STR3##
Musial, Roczniki Chem., 1951, 25, 46-52 (Chem. Abs., 1953, 47, 4885f) synthesized 1,3-derivatives of (i) as illustrated in formula (ii). ##STR4##
Fryer, et al., J. Org. Chem., 1977, 42, 2212-2219 describes the 3,7,9-trisubstituted compound of formula (iii). ##STR5##
Reid, et al., Chem. Ber., 1956, 89, 2684-2687 describes the synthesis of the 1,3-diphenyl derivative of formula (iv). ##STR6##
No pharmacological utility is taught for the 1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-one structures disclosed in the aforementioned references which are of a chemical nature.
Various derivatives of the tetrahydroimidazo[2,1-b]quinazolin-2-one (v) heterocycle have been studied for their platelet inhibition and cardiotonic properties. ##STR7## For example:
Beverung, Jr., et al., U.S. Pat. No. 3,932,407 disclose a series of compounds useful as blood platelet antiaggregative and/or antihypertensive and/or bronchodilator agents of the tetrahydroimidazo[2,1-b]quinazolin-2-one class. Anagrelide (vi), a particularly preferred member of the Beverung, Jr., et al. series, has been studied extensively, e.g., J. S. Fleming, et al., New Drugs Annual: Cardiovascular Drugs, Raven Press, pages 277-294, New York (1983). ##STR8##
Chodnekar, et al, U.S. Pat. No. 4,256,748 describes a series of tetrahydroimidazo[2,1-b]quinazolin-2-ones of the formula (vii) as inhibitors of the aggregation of blood platelets and cardiotonic activity. ##STR9## Representative of the Chodneker compounds are RO 15-2041 (R.sup.4 .dbd.CH.sub.3, R.sup.3 .dbd.H, R.sup.2 .dbd.6--CH.sub.3, R.sup.1 .dbd.7--Br) and RO 13-6438 (R.sup.4 .dbd.CH.sub.3, R.sup.3 .dbd.H, R.sup.2 .dbd.6--CH.sub.3, R.sup.1 .dbd.H).
Jones, et al., U.S. Pat. No. 4,490,371 describes another series of tetrahydroimidazo[2,1-b]quinazolin-2-one derivatives as cyclic AMP phosphodiesterase inhibitors useful as thrombogenic agents. Among the compounds disclosed is the formula (viii) amide, identified in the art as RS82856. ##STR10##
Fried, et al., European Patent Application No. 153152 further describes tetrahydroimidazo[2,1-b]quinozolin-2-ones of formula (ix) as cyclic AMP phosphodiesterase inhibitors useful as antithrombogenic agents. ##STR11##
F. Ishikawa, et al., J. Med. Chem., 28, 1387-1393 (1985) describe amino substituted 1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-2-one compounds having blood platelet aggregation inhibitor activity of formula (x) wherein R.sub.1 is dialkylamino, cyclic amino (e.g., piperidino) and R.sub.2 represents hydrogen, halogen, alkyl, alkoxy. Published European patent application Nos. 129,258 and 133,234 cover this subject matter. ##STR12##